Congenital myasthenic syndrome caused by prolonged acetylcholine receptor channel openings due to a mutation in the M2 Domain of the Epsilon Subunit

OHNO, K.; HUTCHINSON, D.O.; MILONE, M.; BRENGMAN, J.N.; BOUZAT, C.; SINE, S.M.; ENGEL, A.G.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

NATL ACAD SCIENCES

Año: 1995 vol. 92 p. 758 - 762

0027-8424

 In a congenital myasthenic syndrome with a severe endplate myopathy, patch-clamp studies revealed markedly prolonged acetylcholine receptor (AChR) channel openings. Molecular genetic analysis of AChR subunit genes demonstrated a heterozygous adenosine-to-cytosine transversionat nucleotide 790 in exon 8 of the E-subunit gene, predicting substitution of proline for threonine at codon 264 and no other mutations in the entire coding sequences of genes encoding the a, f3, 8, and £ subunits. Genetically engineered mutant AChR expressed in a human embryonic kidney fibroblast cell line also exhibited markedly prolonged openings in the presence of agonist and even opened in its absence. The Thr-264 -> Pro mutation in the E subunit involves a highly conserved residue in the M2 domain lining the channel pore and is likely to disrupt the putative M2 a-helix. Our findings indicate that a single mutation at a critical site can greatly alter AChR channel kinetics, leading to a congenital myasthenic syndrome. This observation raises the possibility that mutations involving subunits of other ligand-gated channels may also exist and be the basis of various other neurologic or psychiatric disorders.